This invention generally relates to compositions and methods for preventing the transmission of sexually transmitted diseases (STDs) and/or reducing the rate of transmission of such sexually transmitted diseases in sexually active individuals. This invention also generally relates to compositions and methods for preventing conception and/or reducing the risk of conception in sexually active females. Although not wishing to be bound by theory, it is believed that the compositions of the present invention, when used within the vagina during sexual intercourse, tend to physically trap and inactivate pathogenic microbes associated with STDs as well as spermatozoa contained in ejaculate that may be deposited within the vagina. The present compositions and methods are especially effective for preventing, or reducing the likelihood of, conception in sexually active females and reducing the risk of being infected by, or of transmitting, sexually transmitted diseases during male/female sexual intercourse. It can, however, be used by heterosexual, homosexual, and bisexual individuals to reduce the risk of being infected by, or of transmitting, a sexually transmitted disease through sexual contact. The present method of this invention is especially effective when used in conjunction with so-called xe2x80x9csafe sexxe2x80x9d techniques.
The method of this invention generally comprises application of an effective amount of the trapping gel within the vagina. Although an applicator can be used to apply the trapping gel within the vagina, such an applicator would be removed before the sexual activity. Preferably, the trapping gel is applied before sexual activity. Although perhaps not as effective, it can also be applied after sexual activity; such delayed application should take place as soon as possible after the sexual activity. Increased protection can be obtained by application of the trapping gel both just before and just after the sexual activity. Although the present trapping gel is designed to provide anti-STD activity during heterosexual activity, it may also provide protection against STDs during other sexual activity (e.g., heterosexual or homosexual anal sex); throughout this specification, a reference to heterosexual intercourse is intended to include other forms of sexual activity.
The trapping gels of the present invention have both antimicrobial and contraceptive activities. The antimicrobial and contraceptive formulations of the present invention generally have fewer side effects than conventional vaginal contraceptives (e.g., nonoxynol-9). For example, the trapping gels useful in this invention are generally not toxic (or only slightly toxic) at their effective levels to natural and beneficial vaginal flora and, thus, do not significantly upset the local microbiological balance. Of course, inclusion of contraceptives such as nonoxynol-9 in the present trapping gels will increase the risk of side effects. Generally, however, such contraceptives can generally be added to the present compositions at lower levels than found in conventional vaginal contraceptives while maintaining their effectiveness. Furthermore, the present compositions are generally not cytotoxic (or at least only minimally so) and do not cause irritation or lesions of the vagina or cervix. In addition, the trapping gels of the present invention assist in maintaining the pH level within the vagina at natural acidic levels (generally about pH of about 3.5 to 4.5) and, therefore, provide even more protection. Maintaining the pH at such acidic levels reduces the risk of conception as well as infection by STD-causing microbes while maintaining local microbiological balance. Moreover, by reducing the risk of damage to the vaginal lining, the risk of infection by STDs, including HIV, is further reduced. Additionally, the trapping gels of this invention may be used to prevent and/or treat vaginitis and/or bacterial vaginosis.
When semen is ejaculated into the vagina, the trapping gel of the present invention causes thickening of the gel/semen mixture, forming a semisolid structure from which ejaculated pathogenic microbes (e.g., STD-causing microbes, including HIV) and spermatozoa cannot escape, or do so only slowly, thereby preventing or significantly reducing migration through the lower genital tract. The trapping gel also tends to harden cervical mucus, thereby preventing or decreasing sperm penetration of the vaginal mucus and obstructing passage through the cervical canal. Additional prevention of STD-infection by the trapping gel arises from the formation of a bio-adhesive, protective barrier over the vaginal lining (e.g., the stratified squamous epithelium) or over the rectal lining in the case of anal sex. To further increase the anti-STDs and/or contraceptive activity of the trapping gels of this invention, microbiocides and/or spermicides (e.g., nonoxynol-9 and others) can be included in the present formulations. It is expected that lower levels of such microbiocides and/or spermicides can be used in the present compositions and methods while maintaining high contraceptive activity, thereby reducing the side effects of such microbiocides and/or spermicides.
In recent years, sexually transmitted diseases (STDs) have become an increasing medical problem and concern throughout the world. The HIV/AIDS epidemic over the last decade or so has significantly and dramatically underscored the threat of STDs to the human population. The best, and perhaps only realistic, approach to this increasing problem of STDs (especially HIV/AIDS) appears to be reducing the risk of transmission of STDs by pathogenic organisms and thus reducing the number of individuals who become newly infected. Even when treatments or cures become available, prevention of infections in the initial instance will likely remain as the first line of defense. For medical, psychological, and economic reasons, it is preferable to prevent the initial infection rather than treating, and even curing, individuals with STDs.
At present, education in regard to STDs, their modes of transmission, and so-called xe2x80x9csafe-sexxe2x80x9d techniques has, at least to some degree in the more developed countries, shown promise in reducing the risks of STD transmission through sexual activity. Screening of the blood supply has helped to reduce the risk of transmission of such STD-causing organisms via blood transfusions and related medical practices. Nonetheless, the spread of such STDs has not been halted to a satisfactory degree even in developed countries with active and progressive education programs. Even with their known effectiveness in preventing STDs, current safe-sex techniques are not always used, or are not always used properly, for many reasons (e.g. carelessness, lack of knowledge, improper techniques, cultural barriers, unplanned or spontaneous sexual activity, and the like). Moreover, even when used, safe-sex techniques (except perhaps abstinence) are not always effective. For example, condoms are generally only about 80 to about 90 percent effective in preventing conception when used alone; in the case of such failures, STD-causing organisms, if present, may pass from one sexual partner to the other.
Various birth control devicesxe2x80x94including barrier methods and vaginal contraceptivesxe2x80x94are currently available. Some of these may, in addition, also have at least some degree of anti-STD activity. For example, condoms can help prevent the transmission of STDs so long as they are properly used and/or they perform properly. Nonoxynol-9, currently one of the most widely used contraceptive agents, is reported, at least in some cases, to reduce the risk of transmission of some STDs. Nonoxynol-9, which is a nonionic detergent with strong surfactant properties, acts, like most other chemical-based contraceptives, by killing or otherwise immobilizing spermatozoa (e.g., spermicidal activity). Nonoxynol-9 is a potent cytotoxic agent which tends to nonspecifically disrupt cell membranes. These properties, however, give rise to some very significant disadvantages. Nonoxynol-9 can injure vaginal/cervical epithelial and other cells at concentrations as low as about 0.0005 percent (in vitro). Clinical studies have confirmed epithelial disruption of the vagina and cervix at the concentrations normally present in vaginal contraceptive formulations (generally greater than about 3 percent nonoxynol-9). Nonoxynol-9 also disrupts the normal vaginal flora which provides a protective mechanism, perhaps by maintaining a low pH, to guard against the invasion of pathogenic microbes. Nonoxynol-9 may also partially dissolve or remove the protective glycoprotein coating in the vagina. The cytotoxic, flora-disruptive, and glycoprotein-removal effects of nonoxynol-9 can lead to vaginal damage or injury, including lesions. Some women are especially sensitive to nonoxynol-9 and manifest these effects with only occasional use. The disruption of these protective mechanisms by nonoxynol-9 can actually increase the risks of STD infections since the breakdown of the protective mechanisms, and especially the occurrence of lesions, allows STD-causing organisms an easier pathway into the cells. Additionally, the disruption of these protective mechanisms by nonoxynol can increase the risk of vaginitis and/or bacterial vaginosis.
Of course, various commercial vaginal creams and ointments are currently available over the counter or by prescription or are in various stages of development. Nonoxynol-9, octoxynol-9, and benzalkonium chloride are generally available as suppositories, inserts, creams, films, foams, and gels. Examples of such commercial products include, for example, K-Y Plus(trademark) (2.2 percent nonoxynol-9; Advanced Care Products, Raritan, N.J.); Encare(trademark) (3 percent nonoxynol-9; Thompson Medical Co., West Palm Beach, Fla.); Gynol II (Advanced Care Products, Raritan, N.J.); Ortho Options Conceptrol (Advanced Care Products, Raritan, N.J.); Semicid (Whitehall Robbins Healthcare, Madison, N.J.); and Advantage-S (Columbia Laboratories, Aventura, Fla.). As discussed above, the levels of nonoxynol-9 or other cytotoxic agents contained in such products are generally disruptive to the vagina and cervix and upset the normal vaginal milieu. Moreover, such formulations have only limited capability, if any, to prevent STD infections. Indeed, many women using such products report burning and pain sufficient to terminate the use of the products. Gels designed to control vaginal pH are also available. For example, Aci-Jel(trademark) (Ortho-McNeil Pharmaceutical Corp., Raritan, N.J.) is a water-dispersible buffered gel having a pH of 3.9 to 4.1 which is used to restore and maintain normal vaginal acidity. Such gels are designed to control vaginal pH and are not designed to prevent STDs and/or conception; these gels do not trap and/or inactivate STD-causing pathogens or spermatozoa.
U.S. Pat. No. 5,439,685 (Aug. 8, 1995) provides a pharmaceutical composition for the prevention of sexually transmitted diseases. These compositions are reported to produce a film or barrier layer over the vagina mucosa which prevents contact of the STD-causing microbes with the vagina surfaces. However, these formulations do not form a semisolid matrix with the ejaculate to effectively trap STD-causing microbes and/or spermatozoa; nor do they cause hardening of cervical mucus to prevent entry of spermatozoa. These gels may also contain cytotoxic agents such as nonoxynol-9, benzalkonium chloride, and sodium cholate which, which in spite of the film or barrier, may still be disruptive to the vagina and cervix. Finally, these gels are designed to be used in conjunction with a vaginal device such as a tampon, unlike the present invention.
More recently, BufferGel(trademark) (ReProtect LLC, Baltimore, Md.), developed at John Hopkins University, is undergoing clinical trials. BufferGel(trademark) is reported to be a negatively charged, non-absorbable high molecular weight polymer gel, designed to maintain vaginal pH below 5 in the presence of semen. As detailed in U.S. Pat. No. 5,617,877 (Apr. 8, 1997), BufferGel(trademark) relies on a polymer comprised of carboxylated monomers (preferably crosslinked polyacrylic acids such as, for example, Carbopol(copyright) polymers (high molecular weight homo- and co-polymers of acrylic acid crosslinked with a polyalkenyl polyether; available from B F Goodrich)) to control the vaginal pH. BufferGel(trademark) does not trap STD-causing microbes and/or ejaculated spermatozoa or harden cervical mucus, thereby allowing the STD-causing microbes and/or ejaculated spermatozoa to readily migrate throughout the lower genital tract. Moreover, the composition is designed to be used with a device to be inserted into the vagina and positioned covering the cervix. To be effective, the device must remain in position covering the cervix. Removal of the device or a shift of its position relative to the cervix can destroy, or at least significantly reduce, its effectiveness. As detailed in the patent, the xe2x80x9cdevice positions advantageous quantities of appropriate buffers in a dome shaped configuration that provides stable positioning of the device around the cervix. The large surface area of the device and its resilient circular shape cause it to project into the posterior vaginal fornix, gently spreading the vaginal mucosa against the surface of the device, thus preventing pooling of the ejaculate in a relatively inaccessible cul-de-sac. The device is highly absorptive, and rapidly sequesters and acidifies both semen and menstrual fluid.xe2x80x9d Of course, the use of such devices in combination with BufferGel(trademark) requires significant skill and motivation by the user to obtain, and maintain, proper placement of the device. Moreover, there is likely to be a reduction of pleasure and sensitivity of the sex act using such a device. Such devices are, therefore, less likely to be used on a consistent basis because of the difficulty of use, especially in cases of xe2x80x9cspontaneousxe2x80x9d sexual activity.
Similar crosslinked polyacrylic acids (i.e., polycarbophil) have also been used for drug (e.g., nonoxynol-9 or progesterone) delivery within the vagina. Robinson et al., J. Controlled Release, 28, 87 (1994).
It would be desirable, therefore, to provide improved compositions and methods which reduce the risk of STD transmission and/or infections during sexual activity. It would also be desirable if such improved compositions and methods also possess contraceptive activity. It also would be desirable if such compositions and methods would not interfere with the natural and protective vaginal mechanisms. It also would be desirable if such compositions and methods can be used to prevent and/or treat vaginitis and/or bacterial vaginosis. It would also be desirable if such compositions and methods would be relatively easy to use and have significantly fewer side effects than currently available methods (i.e., nonoxynol-9 at relatively high levels) so that it would more likely be used on a consistent basis. It would also be desirable if such compositions and methods did not require a physical device to remain within the vagina during use. The present invention, as detailed in the present specification, provides such methods.
This invention generally relates to compositions and methods which prevent and/or reduce the risk of transmission of sexually transmitted diseases through sexual activity and which are also contraceptive. This method is especially suitable for use by heterosexual couples for preventing pregnancy and significantly reducing the risk of being infected by, or of transmitting, a STD through sexual contact. Although this method can be used alone, it is generally preferred that it be used in conjunction with other so-called xe2x80x9csafe sexxe2x80x9d techniques in order to even further reduce the risk of pregnancy and/or STD transmission or infection.
The method of this invention generally comprises the application of an effective amount of the compositions of this invention within the vagina prior to engaging, or as soon as possible after engaging, in sexual activity. The compositions of this invention, in addition to anti-STD activity, act as vaginal contraceptives and generally have fewer side effects than conventional vaginal contraceptives (e.g., nonoxynol-9). The compositions of this invention are designed to form a semisolid matrix when they come in contact with semen ejaculated into the vagina. The semisolid matrix is effective in trapping STD-causing microbes, including HIV, and spermatozoa, and thereby preventing or greatly decreasing their migration through and out of the lower genital tract. Contraceptive activity is further enhanced by making the formulation hypertonic which results in hardening of the cervical mucus, thereby preventing or hindering entry of spermatozoa into the cervix. As those skilled in the art realize, a hypertonic solution or gel generally has a higher level of salts than a reference solution. For purposes of the present invention, the reference solution is normal reproductive tract fluids or vaginal mucus. Reproductive tract fluids generally have an osmolality of about the same as, or higher than, blood plasma and generally in the range of about 300 to about 350 mosmoles/kg. The osmolality of cervical mucus will vary somewhat during the cycle since it becomes thinner during the midcycle (ovulatory period when sperm passage occurs) and thicker during the anovulatory period. If desired, the osmolality of gel can be measured using an osmometer.
Prevention of STD transmission and infection is further enhanced by inclusion of bio-adhesive agents which can form a bio-adhesive film over the vaginal and cervical surfaces (as well as rectal surfaces during anal sex), preventing contact of STD-causing microbes with the walls of the lower genital tract. Finally, the compositions of the present invention help in maintaining a natural pH balance within the vagina even in the presence of semen (normal pH of semen is about 7.2 to 7.8; neutral to slightly basic). Vaginal pH is reported to increase from about 4 to about 6 to 7 shortly after ejaculation during unprotected sex and remains at such high levels for two to eight hours. Reestablishing or maintaining an acidic pH appears to assist in killing, inactivating, and/or immobilizing certain STD-causing microbes (including HIV) and spermatozoa within the vagina, thereby preventing or reducing the risk of STD transmission or infection. Reestablishing or maintaining an acidic pH within the vagina also assists in maintaining the natural and beneficial vaginal flora. Moreover, the protective glycoprotein vaginal coating is not significantly disrupted or impaired. Disruption of the natural vaginal flora and/or removal or disruption of the protective glycoprotein vaginal coating using conventional vaginal contraceptives can lead to irritation of the vaginal wall and/or lesions on the vaginal wall which can make the transmission of STD easier and/or more likely.
The trapping gels of the present invention have a number of other attributes which make them especially useful as anti-STDs agents and/or contraceptives. For example, the gels can be formulated to provide gels which are thick, viscous, smooth, pleasant to feel, and pleasantly acidic in taste. The gels are also water dispersible but retain their viscosity when diluted. The trapping gels of the present invention can also be formulated in rapidly dispersible solid forms (e.g., powders, tablets, and the like; see Example 11) which, when inserted into the vagina, form the desired trapping gel by rapidly disintegrating or dispersing through the action of vaginal or other fluids present within the vagina. Such solid forms are, of course, especially convenient for carrying, for example, in a purse. Of course, other dosage forms of the trapping gels can be used if desired. Suitable dosage forms include, for example, gels, creams, lotions, viscous liquids, tablets, powders, films, suppositories, foams, and the like. Although solid forms (e.g., tablets and powders) will generally contain only small amounts of water, the vaginal or other fluids within the vagina can supply the desired water to form the trapping gel composition. The major components are generally considered safe (U.S.P.-listed or GRAS-listed). The gels can be easily dispensed through a syringe or similar applicator or applied manually or can be in the form of tablets or other solid forms for insertion into the vagina. The gels are designed to provide a controlled release of any active ingredients (e.g., nonoxynol-9) and, therefore, are expected to provide long term efficacy. Through their humectant activity, the gels also increase the moisture level of the vagina, thereby reducing the occurrence of vaginal lesions and increasing the pleasurable aspects of the sexual activity. The gels may also contain lubricants which will also increase the pleasurable aspects of the sexual activity. The gels should also reduce leakage and avoid messiness. Many of the just-mentioned aspects and benefits of the present gel compositions and methods will encourage consistent use, thereby providing even further protection. The gels are also useful as delivery systems for active ingredients with antimicrobial and/or contraceptive properties.
One object of the present invention is to provide an antimicrobial and contraceptive composition that reduces the risk of transmission of, or infection by, a sexually transmitted disease through sexual activity involving a vagina of a female and a penis of a male, said composition comprising (1) a matrix-forming agent, (2) a bio-adhesive agent, (3) a buffering agent, and (4) water; wherein the composition is suitable for application within the vagina; wherein the composition forms a semisolid matrix on contact with semen; wherein the composition causes hardening of cervical mucus; wherein the composition forms a bio-adhesive layer over vaginal surfaces; wherein the composition maintains an acidic vaginal pH of less than about 5 in the presence of semen ejaculated from the male (e.g., before, during, or after the sexual activity); wherein the composition does not significantly impair the natural microbiological balance within the vagina; and wherein the composition is hypertonic. If desired, the antimicrobial and contraceptive composition may also include additional antimicrobial and/or contraceptive agents (e.g., nonoxynol-9, octoxynol-9, benzalkonium chloride, phosphorylated hesperidins, sulfonated hesperidins, polystyrene sulfonates, substituted benzenesulfonic acid formaldehyde co-polymers, and H2SO4-modified mandelic acids, povidone iodine, itraconazole, ketoconazole, metronidazole, clotrimazole, fluconazole, teraconazole, miconazole, tinidazole, iconazole, chloramphenicol, nystatin, cyclopiroxolamine, and the like). Preferably the antimicrobial and contraceptive composition also contains a humectant, a preservative, and/or a lubricant.
Another object of the present invention is to provide a method of reducing the risk of transmission and infection by a sexually transmitted disease through sexual activity involving a vagina of a female and a penis of a male, said method comprising administering an effective amount of an antimicrobial and contraceptive composition within the vagina prior to, or shortly after, sexual activity; wherein the composition comprises (1) a matrix-forming agent, (2), a bio-adhesive agent, (3) a buffering agent, and (4) water; wherein the composition is suitable for application within the vagina; wherein the composition forms a semisolid matrix on contact with semen; wherein the composition causes the hardening of cervical mucus; wherein the composition forms a bio-adhesive layer over vaginal surfaces; wherein the composition maintains an acidic vaginal pH of less than about 5 in the presence of semen ejaculated from the male; wherein the composition does not significantly impair the natural microbiological balance within the vagina (e.g., before, during, or after the sexual activity); and wherein the composition is hypertonic. If desired, the composition may also include additional antimicrobial and/or contraceptive agents (e.g., nonoxynol-9, octoxynol-9, benzalkonium chloride, phosphorylated hesperidins, sulfonated hesperidins, polystyrene sulfonates, substituted benzenesulfonic acid formaldehyde co-polymers, and H2SO4-modified mandelic acids, povidone iodine, itraconazole, ketoconazole, metronidazole, clotrimazole, fluconazole, teraconazole, miconazole, tinidazole, iconazole, chloramphenicol, nystatin, cyclopiroxolamine, and the like). Preferably the antimicrobial and contraceptive composition also contains a humectant, a preservative, and/or a lubricant.
Still another object of the present invention is to provide an antimicrobial and contraceptive composition for reducing the risk of transmission and infection by a sexually transmitted disease through sexual activity comprising (1) about 1 to about 10 percent of one or more matrix-forming agents, (2) about 1 to about 10 percent of one or more bio-adhesive agents, (3) about 1 to about 10 percent of one or more buffering agents, and (4) water; wherein the composition is suitable for application in a vagina; wherein the composition forms a semisolid matrix on contact with semen ejaculated from a male into the vagina; wherein the composition causes hardening of cervical mucus of the vagina; wherein the composition forms a bio-adhesive layer over vaginal surfaces; wherein the composition maintains an acidic vaginal pH of less than about 5 in the presence of semen ejaculated from the male; wherein the composition does not significantly impair the natural microbiological balance within the vagina (e.g., before, during, or after the sexual activity); and wherein the composition is hypertonic. If desired, the antimicrobial and contraceptive composition may also include additional antimicrobial and/or contraceptive agents (e.g., nonoxynol-9, octoxynol-9, benzalkonium chloride, phosphorylated hesperidins, sulfonated hesperidins, polystyrene sulfonates, substituted benzenesulfonic acid formaldehyde co-polymers, and H2SO4-modified mandelic acids, povidone iodine, itraconazole, ketoconazole, metronidazole, clotrimazole, fluconazole, teraconazole, miconazole, tinidazole, iconazole, chloramphenicol, nystatin, cyclopiroxolamine, and the like). Preferably the antimicrobial and contraceptive composition also contains a humectant, a preservative, and/or a lubricant.
These and other advantages of the present invention will be apparent from a consideration of the present specification.
The present invention relates to a trapping gel that, when placed in a body orifice (e.g., vagina), entraps and inactivates spermatozoa and/or sexually transmitted disease (STD)-causing microbes. Although not wishing to be limited by theory, it appears that the formulations of this invention form a semi-hardened or semisolid matrix when exposed to an ejaculate, thereby sequestering spermatozoa and STD-causing microbes. Additionally, the formulations of this invention form a bio-adhesive and essentially impenetrable layer over the surface of the orifice (e.g., vagina and cervical tissue), preventing contact and/or entry of spermatozoa and/or STD-causing microbes. The formulations of this invention are hypertonic; thus, when placed in the vagina, it will sequester water from the mucus in the cervix, and thereby cause the mucus to harden and provide even further protection by preventing or significantly reducing entry of spermatozoa and/or STD-causing microbes into the cervix. These properties, working together, allow for effective entrapment of spermatozoa and/or STD-causing microbes within the vagina and effectively prevent such spermatozoa and/or STD-causing microbes from entering the body either through the vaginal lining or the cervix. The formulation is acid-buffering to maintain the normal vaginal milieu and environment which further assists to inactivate certain STD-causing microbes and spermatozoa; maintaining the normal vaginal milieu also assists in maintaining the body""s natural defenses against certain STD-causing microbes. The formulation may contain sperm- and/or STD microbe-inactivating ingredients such as spermicides and/or microbiocides. The entrapment or immobilization of the spermatozoa and/or STD-causing microbes within the vagina by the formulations of the present invention allows such sperm- and STD microbe-inactivating ingredients sufficient time to more completely inactivate the spermatozoa and/or STD-causing microbes that may be present. The formulations of this invention may also be used to prevent and/or treat vaginitis and/or bacterial vaginosis.
Compositions and methods are provided for (1) prevention and/or reducing the rate or probability of transmission of sexually transmitted diseases between sexual partners when one or more of the partners is infected and (2) prevention and/or reducing the risk of pregnancy. Although it is mainly directed at heterosexual conduct (i.e., male/female vaginal intercourse), the compositions of this invention may also be used by parties engaged in other types of sexual conduct. For example, the compositions of this invention could be used by parties engaged in anal intercourse (male/female or male/male); compositions of this invention intended to be used in anal intercourse are preferably modified to adjust the buffering capacity to pH values normally found in the rectum and by using higher levels of lubricants. Of course, the present method is not limited to use by sexual partners where one of the partners is known to be infected by a STD or at risk for a STD. Rather, this method can be used by sexual partners where neither has a known STD, where one partner has a STD or is at risk for a STD, or where both partners have STDs or are at risk for STDs. Because STDs can be transmitted by an infected partner even before symptoms appear in that party, it is generally recommended that this method be used consistently by sexually active individuals. Of course, since the compositions are contraceptive, they can be use by heterosexual couples where the avoidance of conception is also desired. Moreover, since no one method of preventing the transmission of STDs and/or conceptionxe2x80x94except perhaps complete avoidance of sexual activityxe2x80x94is completely effective, the present method is preferably practiced in conjunction with other methods of reducing the probability of transmission of STDs and/or conception. For example, the present method can be combined with the use of condoms (male or female) and other safe-sex techniques to significantly improve the overall effectiveness as compared to the use of either method alone; such combined methods could go a long way towards eliminating or, at least, significantly reducing the transmission of STDs from one sexual partner to another.
Preventing the initial infection (or reducing the risk of infection), as opposed to treatment of the STD after infection, is critically important medically, psychologically, and economically. Especially for STDs such as HIV/AIDS where there is no known cure, the importance of prevention cannot be overstated. Moreover, as those skilled in the art will realize, the prevention of a disease is generally very different from, and much preferred, as compared to a cure or treatment for the disease (if such cure is even available). For example, AZT and other HIV/AIDS drugs can slow the progression of the disease (and, in some cases and with the use of other strategies, prevent transmission from a HIV-positive woman to her unborn child), but they are not capable of curing the disease. Except in the limited example of an infected mother and her unborn child, the use of such drugs as AZT before the initial infection would not be medically or economically sound practice and would not reduce the risk of infection without subjecting such uninfected individuals to undesired side effects typically associated with the use of these relatively toxic drugs. Likewise, preventing an undesired pregnancy in the first instance, rather than later resorting to medical procedures to terminate the pregnancy, would have significant medical, psychological, and economic, advantages.
The method of the present invention is carried out by applying an effective amount of the trapping gel of the present invention within the vagina. For purposes of this invention, an xe2x80x9ceffective amountxe2x80x9d is an amount of the composition sufficient to (1) cause entrapment of STD-causing microbes and spermatozoa from the ejaculate, (2) form a bio-adhesive film over vaginal surfaces, and (3) maintain a low or acidic pH within the vagina before or after a typical or normal ejaculation by the male during sexual intercourse. A single dose will normally be in the range of about 1 to about 8 ml of the trapping gel; preferably the single dose is about 3 to about 5 ml. Of course, doses higher or lower than these amounts can be used if desired. For purposes of this invention, a xe2x80x9clow or acidic pH within the vaginaxe2x80x9d is generally considered to be within the normal pH level of a healthy female. Preferably, such an acidic pH is less than about 5; more preferably such an acidic pH is in the range of about 3.5 to about 4.5. In other words, besides providing effective entrapment of STD-causing microbes and spermatozoa and the formation of a protective layer of vaginal surfaces, the effective amount of the composition of this invention is an amount which provides sufficient buffering capacity to maintain the pH of the vagina in a low or acidic pH condition in the presence of a typical amount (normally about 1 to about 5.0 ml) of semen from a single xe2x80x9cnormalxe2x80x9d ejaculation having an alkaline pH in the range of about 7.2 to about 7.6. The compositions of this invention are also hypertonic (i.e., having a higher water activity or osmotic pressure relative to the mucus in the cervix in normal, healthy females). Generally, reproductive tract fluids, including cervical mucus, are generally expected to have an osmolality similar to that of blood plasma (normally in the range of from about 290 to about 320 mosmoles/kg). Thus, the osmolality of the trapping gels of this invention, as measured using conventional osmometer, should be higher than the normal osmolality of blood plasma. Although the compositions of this invention are mainly intended to be used in situations where the vagina has a normal pH, it can also be used in cases where the microbiological vaginal balance has already been upset (e.g., active yeast infection); this buffering capacity may assist in returning the vagina to the desired pH range and a more healthy state. In other words, the compositions of this invention may, if desired, be used to prevent and/or treat, for example, vaginal infections, including, for example, vaginitis or bacterial vaginosis.
The trapping gels of the present invention may also be used with conventional birth-control or safe-sex devices. For example, the trapping gels could used in conjunction with condoms (i.e., via lubricants applied to the interior and/or exterior surfaces), diaphragms, cervix caps, or similar products. The trapping gels of the present invention could also, for example, be released into the vagina by hand, suppositories, or conventional tampon or syringe techniques. The method of administering or delivering the trapping gel into the vagina is not critical so long as an effective amount of the trapping gel is delivered into the vagina. The trapping gels of the present invention may also be used for protection during anal intercourse and can be applied using similar techniques.
The trapping gels of the present invention contain (1) a matrix-forming agent, (2) a bio-adhesive agent, (3) a buffering agent, and (4) water. More preferably, the trapping gels of the present invention contain (1) a matrix-forming agent, (2) a bio-adhesive agent, (3) a buffering agent, (4) a humectant, (5) a preservative, and (6) water. If desired, the composition may also include an antimicrobial and/or a contraceptive agent (e.g., nonoxynol-9, octoxynol-9, benzalkonium chloride, phosphorylated hesperidins, sulfonated hesperidins, polystyrene sulfonates, substituted benzenesulfonic acid formaldehyde co-polymers, and H2SO4-modified mandelic acids, povidone iodine, itraconazole, ketoconazole, metronidazole, clotrimazole, fluconazole, teraconazole, miconazole, tinidazole, iconazole, chloramphenicol, nystatin, cyclopiroxolamine, and the like). The trapping gels of the present invention generally contain (1) about 1 to about 10 percent of one or more matrix-forming agents, (2) about 1 to about 10 percent of one or more bio-adhesive agents, (3) about 1 to about 10 percent of one or more buffering agents, (4) 0 to about 2 percent of one or more humectants, (5) 0 to about 2 percent of one or more preservatives, (5) 0 to about 10 percent of one or more antimicrobial or contraceptive agents, and (7) water. More preferably, the trapping gels of the present invention contain (1) about 3 to about 5 percent of one or more matrix-forming agents, (2) about 2.5 to about 6 percent of one or more bio-adhesive agents, (3) about 1 to about 7 percent of one or more buffering agents, (4) about 6 to about 10 percent of one or more humectants preservatives, (5) about 0.1 to about 1 percent of one or more preservatives, (6) about 0.2 to about 5 percent of one or more antimicrobial or contraceptive agents, and (7) water.
Gelling or matrix-forming agents suitable for use in the present invention should be stable over a wide pH range, especially over the normal acidic pH values found in the vagina. Suitable matrix-forming agents include, for example, alginic acid, chitosan, gellan gum, poloxamer, and the like. Alginic acid is the preferred gel hardening or matrix-forming agent and is a generally linear glycouronan polymer containing a mixture of -(1,4)-D-gulosyuronic acid and -(1,4)-D-gulosyuronic acid residues. Generally, the molecular weight of the alginic acid is the range of about 20 to about 300,000 g/mole, preferably in the range of about 20,000 to about 250,000 g/mole, and most preferably about 240,000 g/mole. Alginic acid is expected to form insoluble alginates by interacting with monovalent and divalent cations (especially Na+, K+, and Ca++) in seminal plasma. Since vaginal fluids generally contain very little Ca++, the semisolid matrix is formed only when ejaculate is present. In such cases, the semisolid matrix will trap STD-causing microbes and spermatozoa so that they cannot migrate through the lower female genital tract. Alginates also swell in contact with water, thereby assisting in maintaining the desired gel or matrix structure within the vagina. Of course, alginic acid or salts of alginic acid may also contribute to the acid buffering activity of the trapping gels of the present invention since they have a pH of about 1.5 to about 3.5 in an aqueous solution. Alginic acid may also contribute to the bioadhesive nature of the present formulations and, therefore, assist in providing bioadhesive activity. Because of its high molecular weight, alginic acid will not be absorbed by the body. Thus, its matrix-forming, bioadhesive, and acid-buffering properties will be maintained so as long as the gel remains in the vagina. Moreover, due to the innate bio-adhesive properties of the trapping gel, it will normally remain within the vagina for about 12 to 24 hours (or even longer) if not removed by the woman.
Bio-adhesive agents suitable for use in the present invention include, for example, xanthan gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, chitosan, polycarbophil, carbopol, and the like. The preferred bio-adhesive gum is xanthan gum, a high molecular weight polysaccharide gum containing D-glucosyl, D-mannosyl, and D-glucosyluronic acid residues and varying proportions of O-acetyl and pyruvic acid acetal. The primary structure is a cellulose backbone with trisaccharide side chains; the repeating unit is a pentasaccharide. Generally the molecular weight is greater than about 106 g/mole. Hydroxyethyl cellulose is preferably used in trapping gels that do not contain nonoxynol-9.
Buffering agents are used in the present trapping gel to maintain the pH of the vagina within its normal acidic range (i.e., a pH of less than about 5 and more preferably in the range of about 3.5 to about 4.5) even in the presence of normal amounts of ejaculate. Suitable buffering agents include, for example, lactic acid, citric acid, potassium acid tartrate, benzoic acid, alginic acid, sorbic acid, fumaric acid, ascorbic acid, stearic acid, oleic acid, tartaric acid, edetic acid ethylenediaminetetracetic acid, acetic acid, malic acid, and the like. The acids may be added as free acids, hydrates, or pharmaceutically acceptable salts. Generally the free acids are preferred. Of course, the free acids can be converted to the corresponding salts in situ (i.e., within the vagina). It is generally preferred that several buffering agents are included in the trapping gel of this invention to provide increased buffering capacity. Alginic acid, of course, can function as both a matrix-forming agent and a buffering agent in the present trapping gels. Since alginic acid will not be absorbed by the body, its acid buffering effect will be longer lasting as compared to the other buffering agents which may be absorbed by the body.
The trapping gels of this invention may also include, and preferably do include, humectants. Suitable humectants include, for example, glycerol, polyethylene glycols, propylene glycols, sorbitol, triacetin, and the like. Glycerol, which is the preferred humectant, prevents the formation of a dry film on the gel when placed within the vagina. Glycerol may also act as a lubricant.
The trapping gels of this invention may also include, and preferably do include, a preservative. Suitable preservatives include, for example, benzoic acid, sodium benzoate, methylparaben, ethylparaben, butylparaben, propylparaben, benyalkonium chloride, phenylmercuric nitrate, chlorhexidine, and the like. The preferred preservative is benzoic acid. As discussed above, benzoic acid may also contribute to the buffering capacity of the gel.
The trapping gels of this invention preferably contain alginic acid as the matrix-forming agent; xanthan gum and/or hydroxycellulose as the bio-adhesive agent; a buffering agent selected from the group consisting of lactic acid, citric acid, benzoic acid, potassium acid tartrate; glycerol as the humectant; benzoic acid as the preservative; and water. More preferably, the trapping gels of this invention contain xanthan gum, alginic acid, lactic acid, citric acid, benzoic acid, potassium bitartrate, glycerol, and water. If additional antimicrobials and/or contraceptives are to be included, the trapping gels of the invention more preferably contain xanthan gum, alginic acid, lactic acid, citric acid, benzoic acid, potassium bitartrate, glycerol, water, and a antimicrobial and/or a contraceptive agent selected from the group consisting of nonoxynol-9, octoxynol-9, benzalkonium chloride, phosphorylated hesperidins, sulfonated hesperidins, polystyrene sulfonates, substituted benzenesulfonic acid formaldehyde co-polymers, and H2SO4-modified mandelic acids, povidone iodine, itraconazole, ketoconazole, metronidazole, clotrimazole, fluconazole, teraconazole, miconazole, tinidazole, iconazole, chloramphenicol, nystatin, and cyclopiroxolamine.
Suitable antimicrobial and contraceptive agents include, for example, nonoxynol-9, octoxynol-9, benzalkonium chloride, phosphorylated hesperidins, sulfonated hesperidins, polystyrene sulfonates, substituted benzenesulfonic acid formaldehyde co-polymers, H2SO4-modified mandelic acids, povidone iodine, itraconazole, ketoconazole, metronidazole, clotrimazole, fluconazole, teraconazole, miconazole, tinidazole, iconazole, chloramphenicol, nystatin, cyclopiroxolamine, and the like. Generally these antimicrobial and contraceptive agents, if used, are included in an amount of less than about 12 percent, and preferably at a level of about 2 to about 6 percent. Nonoxynol-9, a well known and commercially available contraceptive agent, may cause vaginal irritation in some women; in those cases it may be preferred to lower the concentration, or even eliminate, nonoxynol-9. Suitable phosphorylated hesperidins and sulfonated hesperidins are described in U.S. Pat. No. 5,925,621 (Jul. 20, 1999). Suitable H2SO4-modified mandelic acids are described in U.S. Pat. No. 5,932,619 (Aug. 3, 1999). Suitable substituted acid formaldehyde co-polymers are described in U.S. Pat. No. 6,028,115 (Feb. 22, 2000); especially preferred co-polymers include the branched poly(methyl ether)hydroquinone sulfonates and derivatives thereof. Suitable polystyrene sulfonates are described in U.S. patent application Ser. No. 09/252,417 (filed Feb. 18, 1999). These patents and patent applications are hereby incorporated by reference. Generally, acid-stable, noncytotoxic agents such as H2SO4-modified mandelic acids and branched poly(methyl ether)hydroquinone sulfonates and derivatives thereof, are preferred.
The trapping gels of this invention are prepared using conventional gel preparation techniques. It is important, however, to ensure that the buffering agents are fully solubilized in the final product and that the entrapment of air in the gel is avoided or at least kept to a minimum. To reduce the entrapment of air in the gel, it is generally preferred that the less hydrophilic agents (e.g., alginic acid) are added in small increments. Alternatively, the trapping gels of this invention can also be prepared in readily dispersable solid forms (e.g., powders, tablets, and the like) which can be converted to the desired gel consistency by action of aqueous based fluids external to or within the vagina when desired. As those skilled in the art will realize, the methods for preparing the trapping gels of this invention can be modified for batch, semi-continuous, or continuous operation so long as the resulting trapping gels have the desired and beneficial properties described herein.
For vaginal heterosexual intercourse, the trapping gel could be inserted into the vagina prior to intercourse. For anal intercourse (heterosexual or homosexual), the trapping gel could be insertted into the rectum prior to intercourse. For either vaginal or anal intercourse, the trapping gel could also act as a lubricant. For added protection it is generally preferred that the trapping gel be applied-before intercourse or other sexual activity and that, if appropriate, a condom be used. For even further protection, the trapping gel can be reapplied as soon as possible after completion of the sexual activity.
If desired, flavorants, scents, fragrances, and colorants can be incorporated into the trapping gel so long as they do not interfere with the protection afforded by the trapping gel. Indeed, incorporation of such flavorants, scents, fragrances, and colorants into the compositions of this invention may provide further protection by increasing the probability that the trapping gel will be used during sexual activity.
One advantage of the present method is that it can be used for protection during a wide variety of sexual activities (vaginal or anal) by heterosexuals, bisexuals, and homosexuals. Another advantage of the present method of reducing the transmission of STDs is that this method can be implemented and/or used most easily by the party being penetrated. Thus, a woman could use the present method to protect herself (as well as her partner) with or without the partner""s knowledge of the method being used. Moreover, the partner would not be required to rely on his or her partner""s claim of being STD-free or agreement to use condoms or other barrier devices for protection. Either or both sexual parties (especially the female participant) could initiate and implement the use of the present method prior to, or after, the sexual encounter. Preferably the method is used before the sexual activity and most preferably both before and after the sexual activity. Although use only after the sexual activity would provide less protection, it would still be desirable to implement this method afterwards if the method was not used prior to the sexual activity for any reason (e.g., in cases of rape). Of course, the sooner this method is initiated after the sexual activity the better. Preferably the method is initiated within one hour, more preferably within 15 minutes, and most preferably almost immediately after the sexual activity. Even after periods greater than these, however, the use of this method as soon as possible after the sexual activity may provide at least some protection (as compared to no treatment).
Still another advantage of the present invention is that, in contrast to other protective methods which rely only on a cytotoxic compound (e.g., nonoxynol-9), the trapping gel used in this invention does not significantly affect or inhibit the growth characteristics of the normal vaginal flora or otherwise significantly irritate the vaginal tissue when used at inhibitory, noncytotoxic, or clinical concentrations. This benefit is at least partially due to the absence of cytotoxic agents in the present compositions. Additionally, even when nonoxynol-9 is included in the present compositions, the adverse characteristics of nonoxynol-9 are less noticeable since (1) the required level of nonoxynol-9 can reduced since the trapping gel has its own contraceptive activity and (2) the bioadhesive nature of the composition affords protection of the vagina lining by reducing the contact of the nonoxynol-9 with the vagina lining. Thus, the beneficial components of normal vaginal flora are generally not disrupted by the use of the present invention. Significant inhibition or modifications of the vaginal flora or other irritations (such as when relatively high amounts of nonoxynol-9 are used in conventional contraceptives) can lead to increased risks of infections (both STD and non-STD types), unusual discharges, general discomforts, and the like, which, in turn, can lead to a reluctance to use or fully take advantage of the protective method. Moreover, the compositions offer the added benefit that they may also be used to prevent and/or treat vaginitis and/or bacterial vaginosis.
By avoiding or reducing the intensity of these effects on the vaginal flora and tissue, the present method is more likely to be used on a consistent basis. By reducing the number of unprotected sex acts (preferably to zero) and encouraging the use of the methods of this invention both before and after each sex act, the overall degree of protection should be significantly increased. By avoiding or reducing vaginal irritations and especially lesions on the vaginal walls (or rectum lining in the case of anal intercourse), the transmission of STD should be further reduced since transmission of STD-causing organisms is generally easier where damage to the cell walls has occurred. Thus, improvements in ease of use, reduction in side effects, ability to be initiated by the party to be penetrated, the ability to be used for different and varied sexual activities, and the ability to maintain normal vaginal flora during use give the compositions and methods of the present invention significant advantages as a contraceptive and/or anti-STD method.